The biocompatibility of materials and devices exposed to vital processes of the body is critical to their utility in therapeutic applications. More than 3 million people in the United States have long-term biomedical implants, including breast prostheses, joint replacements, vascular grafts, pacemakers and catheters, in which therapeutic efficiency is determined in part by the duration of the implant. If the exposed surfaces of these prostheses are not biocompatible, adverse reactions associated with rejection of the implant such as inflammation, necrosis, hemolysis, complement activation, cell adhesion, protein adsorption, thrombus formation, anaphylaxis, fever, calcification, rigidity, phagocytosis, antibody generation, neointimal proliferation, platelet aggregation, fibrosis, coagulation, and infection are frequent and sometimes life-threatening immune responses that may be elicited by a foreign entity. The classical foreign body reaction may not trigger the foregoing response, but will impair or occlude the function of the prosthesis.
Disruption of the endothelium is a potent stimulus for neointimal proliferation, a common mechanism underlying the restenosis of atherosclerotic vessels after balloon angioplasty. (Liu et al., Circulation, 79:1374-1387, 1989.) In addition, chronic inflammatory responses, accompanied by macrophage and/or foreign body giant cell accumulation, may give rise to accelerated calcification, bioprosthesis degeneration, stress cracking, or hydrolysis of exogenous synthetic polymers used in device manufacture. The implant may be poorly integrated into the tissue, and undesirable tissue contracture may result.
Biocompatible materials are constructed of synthetic polymers that are relatively inert, unreactive, and non-toxic. For example, polymers such as polyolefins are used in tubings, shunts, sutures and prosthetic valve structures. Polymethacrylates are used in the construction of membranes, controlled release hydrogels, and as vascular prosthesis coatings. A general description of many synthetic polymers useful in prosthesis construction is given in Implantation Biology: The Host Response and Biomedical Devices, R. S. Greco, Editor, CRC Press, Boca Raton, Fla., 1994, p.13 et seq.
In situations where bioincompatibility cannot be overcome, as where heterologous proteins or foreign body antigenic determinants are present, surfaces may be rendered more biocompatible by partial enzymatic hydrolysis of the antigenic determinants or by masking of such determinants by covalent attachment of exogenous or endogenous polymers such as polyethylene glycol (PEG) or albumin, respectively. The resultant extended circulating lifetime of heterologous cells or cellular components derivatized in this way may improve the adequacy of drug delivery, reduce the metabolic demand on the body, or prevent undesirable blockade of the reticuloendothelial system.
The term bioprosthesis refers to devices derived from biological tissue that is treated to impart in vivo durability. In this process, the treatment invalidates the regenerative properties of the tissue. This characteristic distinguishes bioprostheses from treatments which are meant to retain the cell-regenerative capability of the tissue, such as cryopreservation. Examples of bioprostheses include heart valves, vascular grafts, biohybrid vascular grafts, ligament substitutes, and pericardial patches. When animal tissue is used, it is termed a xenograft, while with human tissue, it is either an autograft (derived from the patient) or a homograft.
Many prosthetic implants are fabricated from donor tissues. These tissues must be stabilized to prevent their disintegration, since the collagen component begins to deteriorate almost at once. Methods for stabilization of collagenous tissue are available. (Khor, E., "Methods for the treatment of collagenous tissues for bioprostheses", Biomaterials, 18: 95-106, 1997.) Stabilizing tissue involves a process yielding a non-viable biohomologous material by promoting bonds between functional groups of the amino acids contained in the tissue. Chemical methods typically utilize bifunctional reagents that interact with collagen at two different sites to give rise to cross-links between two collagen molecules.
One of the most widely used reagents for tissue treatment is glutaraldehyde. (Jayakrishnan A, Jameela SR, "Glutaraldehyde as a fixative in bioprostheses and drug delivery matrices", Biomaterials, 17: 471-484, 1996.) Since 1960, when this chemical agent was first used, many variations and conditions have been applied to optimize its efficiency. In fact, glutaraldehyde is the only agent used commercially to treat bioprosthetic tissues.
Despite its broad utility, glutaraldehyde has a number of shortcomings. The most serious of these is tissue calcification after implantation, a process that is the predominant cause in the failure of porcine aortic valves and bovine pericardium bioprostheses.
Attempts to control calcification include strategies for interrupting or retarding one or more steps in the calcification process. For example, the use of surfactants in tissue treatment is believed to control calcification by removing phospholipids. Other agents which have been employed to increase biocompatibility include sole or continued use of diphosphonates, amino-oleic acid, dimethyl sulfoxide, polyglycidyl ethers, and metal ions. However, none of these treatments has proven sufficiently beneficial to gain regulatory approval and general clinical use, and their applications are confined to laboratory models.
If these strategies are not used, these materials, bioprostheses, or moieties, like any foreign body, trigger acute inflammatory responses that may be followed by chronic inflammation and rejection. (Tang, L, Eaton, JW, "Inflammatory Responses to Biomaterials", Am. J. Clin. Pathol., volume 103 (no. 4), 466-471, 1995.) In general, in these processes a layer of host proteins accumulate on the surface and rapidly denature and degrade. As a result, large numbers of phagocytic cells are attracted to and bound to the site. These phagocytes, perhaps with the collaboration of other cells, initiate inflammatory and fibrotic responses that have both short- and long-term adverse effects on the host.
New approaches are needed for rendering surfaces biocompatible. This need extends to both artificial prosthetic surfaces and also to bioprosthetic tissues, for methodology by which bioprosthetic tissues may be treated to maintain structural and functional integrity for long periods of time following implantation in vivo.